The mechanism(s) by which neurons are damaged by HIV-1 infection, leading to HIV-associated dementia remain unresolved. We have recently shown that neurons are killed by HIV-1 through a novel death- signaling pathway, which leads to neuronal apoptosis and neurodegeneration. In this pathway, matrix metalloproteinase (MMP)-2, released from HIV-infected or -activated macrophages, cleaves the chemokine, stromal cell-derived factor (SDF)-1. Cleaved SDF-1 (C-SDF) is highly neurotoxic, acting via a putative G protein-coupled receptor. Our studies also show that C-SDF also induces expression of pro-inflammatory genes in monocytoid but not astrocytic cells. Our working hypothesis is that proteolytic cleavage of SDF-1 results in a highly neurotoxic and neuro-inflammatory molecule (C-SDF), which causes neuronal apoptosis, mediated by a novel cell membrane receptor that triggers a distinct response phenotype. Thus, the overarching objective of this proposal is to define the molecular structure and abundance of the SDF-derived neurotoxic and neuro-inflammatory ligand and to characterize its cognate receptor with the long-term objective of delineating the molecular mechanisms by which neurons are killed by C-SDF. We will characterize the relative expression of C-SDF together with defining the molecular structures of the C-SDF immunoreactive protein in relation to HIV-associated dementia. Comparative molecular domains within C- SDF will be defined in terms of their neurotoxic and neuroinflammatory properties. The C-SDF receptor(s) will be characterized by ligand binding studies and sequence determination. The response profiles of the C- SDF receptor(s) in neurons and monocytoid cells will be characterized, permitting us to develop rational diagnostic and therapeutic strategies for HIV-associated dementia. Lay Summary: HIV-associated brain disease represents a global public health problem, which also heralds reduced survival during HIV infection. The studies proposed herein will define the mechanisms by which a host protein, stromal cell-derived factor-1, in the brain is degraded by HIV infection, resulting in a highly neurotoxic molecule. The information derived from this proposal will be applicable to the prevention and treatment of HIV-associated brain disease. [unreadable] [unreadable]